The migration of lymphocytes from the peripheral blood across the blood brain barrier has been reported to initiate the development of several central nervous system (CNS) inflammatory diseases. Lymphocyte entry into the CNS is mediated by cellular adhesion molecules (O'Neill et al., Immunology 72:520-525 (1991); Raine et al., Lab. Invest. 63:476-489 (1990); Yednock et al., Nature 356:63-66 (1992); Baron et al., J. Exp. Med. 177:57-68 (1993); Steffen et al., Am. J. Path. 145:189-201 (1994); Christensen et al., J. Immunol. 154:5293-5301 (1995)).
Cellular adhesion molecules present on the cell surface mediate the direct binding of one cell to another (Long et al., Exp. Hematol. 20:288-301 (1992)). The integrin and immunoglobulin supergene families of adhesion molecules regulate lymphocyte traffic into the CNS (Hemler et al., Annu. Rev. Immunol. 8:365-400 (1990); Springer et al., Cell 76:301-314 (1994); Issekutz et al., Curr. Opin. Immunol. 4:287-293 (1992)). Adhesion molecules have been widely reported to mediate inflammatory and autoimmune diseases, for example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, tissue transplantation rejection, and tumor metastasis.
Integrins are heterodimers of non-covalently linked α and β chains (Hemler et al., Annu. Rev. Immunol. 8:365-400 (1990)). The α4β1 (also called very late activation antigen-4 VLA-4) and α4β7 integrins are present on the surface of most types of white blood cells, where they mediate white cell binding to endothelial cells by interacting with their cognate receptors, vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cellular adhesion molecule-1 (MAdCAM-1), on the endothelial cell surface. Integrins are believed to play an important role in immune cell adhesion to the endothelial cell layer on blood vessels, facilitating their subsequent migration into inflamed tissues. Several studies implicate VLA-4 and, in particular the α4 integrin subunit, in CNS inflammation (Yednock et al., Nature 356:63-66 (1992); Baron et al., J. Exp. Med. 177:57-68 (1993); Steffen et al., Am. J. Path. 145:189-201 (1994); Christensen et al., J. Immunol. 154:5293-5301 (1995). It has also been reported that VCAM-1 expression is elevated in inflamed brain tissue relative to normal brain tissue (Cannella and Raine, Ann. Neurol. 37:424-435 (1995); Washington et al., Ann. Neurol. 35:89-97 (1994); Dore-Duffy et al., Frontiers in Cerebral Vascular Biology: Transport and Its Regulation, 243-248 (Eds. Drewes & Betz, Plenum, N.Y. 1993)).
The interaction between α4β1 and its targets is a component of the inflammation that takes place in the CNS of patients with multiple sclerosis (MS). Under normal conditions, VCAM-1 is not expressed in the brain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulated on endothelial cells and on microglial cells near the sites of inflammation (Elices et al., Cell 60:577-584 (1990); Lobb and Hemler, J. Clin. Invest. 94:1722-1728 (1994); Peterson et al., J. Neuropathy Exp. Neurol. 61:539-546 (2002)). Further, osteopontin, which exhibits many properties of a proinflammatory cytokine, is also upregulated in MS lesions (Chabas et al., Science 294:1731-1735 (2001)).
MS is a serious and disabling inflammatory and autoimmune disease of young adults, with a peak age of onset in the third decade of life. Most individuals present with the relapsing-remitting form of the disease and experience recurrent attacks, which, over time, result in accumulating permanent physical disability and cognitive decline. About 70% of these individuals will eventually enter a phase of progressive neurological decline (secondary progressive MS), with or without superimposed relapses. Current treatments are minimally effective for secondary progressive MS. The majority of patients suffer permanent neurological dysfunction and, on average, have a life expectancy of six to seven years after the onset of disease.
Currently, four therapies are approved in the United States for the treatment of relapsing forms of MS. The interferons, Betaseron® (interferon β-1b SC (subcutaneous)), AVONEX® (interferon β-1a IM (intramuscular)), and Rebif® (interferon β-1a SC), are cytokines with antiviral, antiproliferative, and immunomodulatory activities. Copaxone® (glatiramer acetate) is a mixture of synthetic polypeptides with a poorly understood mechanism of action. The β-interferonscan produce serious adverse events and some evidence suggests that copaxone is ineffective (Munari, et al., The Cochrane Library, Issue 1, Chichester, UK: John Wiley & Sons, Ltd. (2004)).
Serious adverse events of β-interferons include rare reports of hypersensitivity reactions, depression and suicide, decreased peripheral blood counts, hepatic injury, cardiomyopathy, and various autoimmune disorders (Betaseron Package Insert, 2003; Rebif Package Insert, 2004; AVONEX® Package Insert, 2005). The development of neutralizing antibodies to interferons is associated with a loss of efficacy. Antibodies that develop to a β-interferon cross-react with other interferons leading to loss of efficacy for the entire class in such patients (IFNB MS Study Group, Neurology 47:889-894 (1996); PRISMS Study Group, Neurology 56:1628-1636 (2001); Kappos et al., Neurology 65:40-47 (2005)). As a result, in the United States alone, over 50,000 patients who were previously treated no longer receive therapy. Thus, there is a large group of patients with active MS who are currently not receiving any approved therapy.
Among those patients who do receive treatment, a significant number continue to experience disease activity, as observed clinically and by magnetic resonance imaging (MRI). Although a variety of therapeutic strategies are currently used in clinical practice to manage breakthrough disease while on treatment (e.g., switching therapy, changing dose and frequency of interferon, combination therapy), the similar efficacy between available medications and lack of clinical data demonstrating the effectiveness of any of these strategies in breakthrough patients makes the decision of what to do for these patients largely empirical. Each of the partially effective approved medications leads to an approximately 30% reduction in relapse rate and limited impact on disability progression (IFNB MS Study Group, Neurology 43:655-661 (1993); Jacobs et al., Ann. Neurol. 39:285-289 (1996); PRISMS Study Group, Lancet 352:1498-1504 (1998)); Johnson et al., Neurology 45:1268-1276 (1995)). Data from the Phase 3 trials of β-interferon in MS show that 62% to 75% of subjects experienced at least one relapse during these 2-year trials despite interferon treatment (IFNB MS Study Group, Neurology 43:655-661 (1993); Jacobs et al., Ann. Neurol. 39:285-289 (1996); PRISMS Study Group, Lancet 352:1498-1504 (1998)). Similarly, 66% of subjects in the Phase 3 MS trial of glatiramer acetate experienced at least one relapse during the 2-year period, a proportion that was not significantly different from placebo (Johnson et al., Neurology 45:1268-1276 (1995)).
Progressive Multifocal Leukoencephalopathy (PML) is a severe, rapidly progressive disease that destroys the myelin coating which protects nerve cells. PML occurs almost exclusively in severely immunosuppressed patients and is frequently associated with lymphoproliferative and other chronic diseases, such as AIDS, Hodgkin's disease, chronic lymphocytic leukemia, sarcoidosis, tuberculosis, systemic lupis erythematosis, and organ transplantation. JC virus (JCV) is the etiological agent of PML and may result from a primary infection or follow reactivation of latent virus.
Natalizumab, an α4-integrin antagonist, has been used successfully to treat diseases with inflammatory and/or autoimmune components, for example, MS, Crohn's Disease, and rheumatoid arthritis. Natalizumab is a humanized IgG4κ monoclonal antibody directed against the α4-integrins α4β1 and α4β7. Chain swapping between natalizumab and other IgG4 molecules may affect the pharmacokinetics of natalizumab. Differences in the concentration of IgG4 between patients or within a patient over time may lead to differences in the concentration of bivalent natalizumab delivered over a dosing period. This may lead to variation in safety and/or efficacy between patients or within a patient over successive dosage periods.
Variation in IgG4 levels may also lead to excessive natalizumab activity in certain patients. This may lead to an increased risk of infection in those patients. For example, there are three known cases of PML occurring during or after administration of natalizumab, two proved fatal and one patient recovered. All three cases occurred in patients on concomitant medications which may have contributed to immunosuppression.
Thus, there is a need in the art for determining the relationship between IgG4 levels and natalizumab pharmacokinetics, and for adjusting natalizumab dose and dosage interval in certain patients in view of this information to improve the safety and/or efficacy of natalizumab treatment.